Scrapie of sheep is the prototype of a group of diseases collectively designated the transmissible spongiform encephalopathies (TSE). TSE diseases affect a wide range of species including sheep, cattle, mink, humans and others. The newest member of the group, bovine spongiform encephalopathy (BSE) or "mad cow disease" is believed to have been derived from scrapie infected sheep. There is no evidence that sheep scrapie infects humans. However, passage of sheep scrapie through cattle may have altered its biological characteristics possibily making BSE transmissible to humans. Interspecies transmission of TSE diseases is difficult to predict but probably involves complex interactions between specific protein molecules of the species considered and in particular a protein designated prion protein (PrP). The overall objective of this project is to determine how PrP and other factors and conditions govern transmission from one species to another. Strategies to interfere with the transmission or disease process will be developed based on these findings.